DiagnosisClinical DiagnosisMultiminicore disease (MmD) has a wide clinical spectrum with four distinct phenotypes (see Clinical Description). Clinical findings that may support the diagnosis of MmD include the following:Weakness (predominantly axial and proximal) and hypotonia; scoliosis and respiratory difficulty occur in approximately two-thirds of affected individuals. Onset typically at birth or during infancy; sometimes in childhood TestingMuscle BiopsyThe diagnosis of MmD is based on the presence of multiple "minicores," small zones of sarcomeric disorganization and/or diminished oxidative activity that correlate with lack of mitochondria in muscle fibers. Unlike the cores typical of central core disease, minicores affect both type I and type II fibers and are short in length, spanning only a few sarcomeres in the fiber longitudinal axis.Note: Because minicores are not specific to MmD, the diagnosis of MmD is based on the presence of minicores in a large proportion of muscle fibers associated with static or slowly progressive weakness and absence of findings diagnostic of other disorders.H&E staining reveals moderate to marked variability in fiber size; the number of internal nuclei may be increased. Fat and/or connective tissue is normal or mildly increased. Myofibrillar ATPase staining may be normal, but frequently shows type I fiber predominance. Relative hypotrophy of type I fibers is often observed, with mean diameter of type I fibers smaller than that of type II fibers in many cases. Oxidative stains (NADH-TR, succinate dehydrogenase, cytochrome oxidase) reveal multiple small focal lesions ("minicores") of sarcomeric disorganization and/or reduced or absent oxidative activity in 60%-90% of fibers. These focal lesions are generally round, small, variable in size, multiple, and randomly distributed with poorly defined boundaries. The cores are often oriented transversely to the fibers and may span up to 15 to 20 sarcomeres [Ferreiro et al 2000, Jungbluth et al 2000]. While cytochrome oxidase staining is specific for lack of mitochondria, NADH-TR staining reveals both the lack of mitochondria and the myofibrillar disruption characteristic of "unstructured cores." Immunohistochemistry. Reliable (but nonspecific) markers for MmD [Fischer et al 2002, Bönnemann et al 2003] include the following: Anti-titin antibodies reveal disorganization of the normal striated pattern in unstructured cores. Anti-desmin antibodies show increased reactivity in the core lesions. AlphaB-crystallin, heat shock protein 27, and filamin C have shown increased immunoreactivity in core lesions (minicore, central core, and target fibers). Anti-alpha-actinin and anti-actin antibodies do not reveal any abnormalities [Ferreiro et al 2000]. Electron microscopy. Cores are typically unstructured and often circular. Their appearance ranges from focal areas of Z line streaming and reduced or absent mitochondria to severe focal disorganization of myofibrillar structure [Ferreiro et al 2000, Jungbluth et al 2000]. "Structured" minicores, exhibiting intact sarcomeres and only absence of mitochondria, may be more difficult to detect [Ferreiro & Fardeau 2002]. Biochemical and Electrophysiologic Studies Studies may suggest a myopathic process but have a limited role in making the diagnosis.Serum creatine kinase concentration is normal or slightly elevated. EMG ranges from normal to nonspecifically abnormal, with findings such as low-amplitude polyphasic potentials of short duration. The absence of a neurogenic pattern eliminates the possibility of denervation, which may also lead to presence of core lesions. Molecular Genetic TestingGenes. Mutations in two genes are known to cause MmD in approximately 50% of affected individuals.Evidence for locus heterogeneity. Further genetic heterogeneity is suggested: a family with dilated cardiomyopathy and multiple minicores and another family with overlapping features of Laing distal myopathy and MmD have been described, both with heterozygous MYH7 mutations [Cullup et al 2012]. Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Multiminicore DiseaseView in own windowGene SymbolProportion of MmD Attributed to Mutations in This GeneTest MethodMutations Detected Test AvailabilitySEPN1 30%-54% ^{1Sequence analysisSequence variants 2Clinical UnknownDeletion / duplication analysis 3Unknown; none reported 4RYR1 UnknownSequence analysisSequence variants 2Clinical UnknownSequence analysis of select exons 5Sequence variants in select exons 2UnknownDeletion / duplication analysis 3Unknown; none reported 31. Autosomal recessive SEPN1 mutations account for approximately 30% of all MmD and approximately 50% of classic MmD [Ferreiro et al 2002b]. An estimated 40% of individuals with SEPN1 mutations are compound heterozygotes.2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.4. No deletions or duplications involving SEPN1 or RYR1 have been reported to cause multiminicore disease.5. Exons sequenced may vary by laboratory.Test characteristics. Information on test sensitivity and specificity and other test characteristics can be found at www.eurogentest.org [Lillis et al 2012 (full text)]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. MmD is a clinicopathologic entity that requires histopathologic examination of a muscle biopsy for the diagnosis to be made. Clinical evaluation includes the following:Personal medical history and physical examination, with particular attention to features of congenital myopathy or muscular dystrophy (e.g., weakness, hypotonia, failure to thrive, scoliosis) Family history, with particular attention to features of congenital myopathy or muscular dystrophy Genetic diagnosis requires molecular genetic testing of SEPN1 and RYR1.Because the majority of individuals with MmD have a mutation in SEPN1, sequence analysis should be done first. If no SEPN1 mutations are identified, sequence analysis of RYR1 should be considered, particularly for those individuals with non-classic forms of MmD. Although no deletions or duplications of either SEPN1 or RYR1 have been reported to date to cause MmD, deletion/duplication analysis of each of these genes could be considered in an individual with features of MmD in whom causative mutations in SEPN1 and RYR1 have not been identified through sequence analysis.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersSEPN1 Congenital fiber-type disproportion (CFTD) is a type of congenital myopathy characterized by hypotonia and mild-to-severe generalized muscle weakness at birth or within the first year of life. The diagnosis is made on muscle biopsy showing type 1 fibers that are at least 12% smaller than the mean diameter of type 2A and/or type 2B fibers in the absence of other significant pathologic findings (e.g., nemaline bodies, cores, or central nuclei). In a recent study [Clarke et al 2006]: Two sibs with CFTD homozygous for a c.943G>A mutation in SEPN1 had clinical findings similar to those of SEPN1-related myopathy. Three women in one family who were homozygous for the c.943G>A mutation had similar clinical findings. Only one had a muscle biopsy; it revealed type 1 fibers to be 10.5% smaller than type 2 fibers (for the diagnosis of CFTD, the type 1 fibers should be >12% smaller), consistent with nonspecific myopathy. No histopathologic features of MmD, RSMD, or desmin-related myopathy were found. It is important to remember that a few cases of CFTD and centronuclear myopathy may show features consistent with MmD on ultrastructural examination [Nadaj-Pakleza et al 2007].Desminopathy. SEPN1 mutations have been identified in individuals with desmin-related myopathy with Mallory body-like inclusions [Ferreiro et al 2004] (see Myofibrillar Myopathy). The clinical presentation is similar to that of MmD/RSMD; on muscle biopsy, hyaline plaques that are devoid of any NADH/SDH activity are seen in up to 10% of fibers under light microscopy. Ultrastructurally, these represent intramyofibrillar inclusions arranged in bundles composed of helical filaments 10-12 nm in diameter and surrounded by electron-dense amorphous material. RYR1Central core disease (CCD) is most often caused by autosomal dominant mutations in RYR1. The majority of CCD-causing mutations are located in the C-terminal region (last 15 exons), which contributes to the formation of the Ca2+ (calcium)-conducting pore [Monnier et al 2001, Wu et al 2006]. Significant clinical and pathologic overlap between CCD and MmD has been identified in individuals who have homozygous or compound heterozygous mutations in RYR1: One family in whom muscle fibers showed coexistence of minicores, central cores, and a few rod-like structures had a homozygous RYR1 mutation in exon 101 [Jungbluth et al 2002]. Another family homozygous for an RYR1 mutation in exon 71 had three affected children with a moderate form of minicore disease with hand involvement. Initial biopsy results for this family were consistent with MmD but subsequent biopsy showed progression to lesions typical of CCD [Ferreiro et al 2002a]. Ten individuals in whom muscle biopsy revealed significant overlap between central cores and minicores were identified to carry compound heterozygous RYR1 mutations distributed throughout the gene. Nine of these ten affected individuals had opthalmoplegia [Monnier et al 2008].Malignant hyperthermia susceptibility (MHS) is caused by RYR1 mutations predominantly in the N-terminal region of the gene, affecting the cytoplasmic domain of the protein that possibly interacts with dihydropyridine receptor. Approximately 50% of all reported MHS is caused by RYR1 mutations. Malignant hyperthermia is also associated with mutations affecting the central domain and more recently the RYR1 C-terminal region [Galli et al 2002]. Multiple minicores have been described in a small proportion of individuals with MHS (2.6%; n=534) [Guis et al 2004]. This study also reported a large family of 17 people with MHS, 16 of whom had multiminicores in muscle fiber and two missense mutations of RYR1 on the same allele in exons 50 and 53. CFTD resulting from biallelic RYR1 mutations has been identified by a recent study [Clarke et al 2010]. RYR1 mutations were responsible for 10%-20% of the individuals with CFTD, making this the second most common cause (after TPM3). Individuals with CFTD who have ophthalmoplegia are more likely to have RYR1 mutations. Reduced ryanodine channel activity as a result of low protein expression has been postulated in some patients with recessive RYR1 mutations [Monnier et al 2008]; however, the mechanism for type I fiber hypotrophy associated with CFTD is unknown.Centronuclear myopathy (CNM). Mutations in RYR1 have been recently identified as a common cause of CNM, further expanding the disease spectrum resulting from RYR1 mutations [Wilmshurst et al 2010]. While the majority of mutations were present as compound heterozygous changes, the detection of only a single RYR1 mutation inherited from an asymptomatic parent was found in a few families, which could represent either monoallelic RYR1 expression or missed promoter mutations/copy number variations in the second allele. Disease severity in individuals with NM who have either single or homozygous/compound heterozygous RYR1 mutations is extremely variable, and like CFTD and core myopathies, opthalmoplegia is a common finding.A missense RYR1 mutation was reported with dominant congenital myopathy in a family with both nemaline bodies and cores [Scacheri et al 2000].}

Natural HistoryMultiminicore disease (MmD) is characterized by axial and proximal muscle weakness. It is usually slowly progressive; however, fatal cases have been described. High-arched palate and chest deformities are common.MmD is broadly classified into four forms [Ferreiro et al 2000, Jungbluth et al 2000, Ferreiro & Fardeau 2002, Nadaj-Pakleza et al 2007]:Classic form Moderate form, with hand involvement Antenatal form, with arthrogryposis multiplex congenita Ophthalmoplegic form In all forms, males and females are equally affected.Classic MmD (75%) Characteristic featuresOnset is usually congenital or occurs in early childhood with neonatal hypotonia and delayed motor development including head lag, a common and early sign. Axial muscle weakness leads to development of scoliosis and major respiratory involvement in approximately two thirds of individuals. Scoliosis develops at a mean age of 8.5 years and is generally cervicodorsal and progressive [Ferreiro et al 2000]. Varying severity of spinal rigidity is present. Rigid spine muscular dystrophy (RSMD), characterized by limited flexion of dorsolumbar and cervical spine (caused by contractures of spinal extensor muscles) is now considered a form of classic MmD. The majority of individuals with these findings have SEPN1 mutations and minicores on muscle biopsy [Moghadaszadeh et al 2001, Ferreiro et al 2002b]. Strength of trunk and neck flexors is usually scored 1 to 2 out of 5, pelvic and shoulder girdle muscles 3 to 4, and distal muscles normal or only moderately weak (3+ to 5). Individuals are usually ambulatory, as limb muscle strength is relatively preserved. Facial muscle strength ranges from normal to severe weakness; extraocular muscles are spared. Cardiac. Cardiac involvement (right ventricular failure, cardiomyopathy) secondary to respiratory impairment is common. Mitral valve prolapse is occasionally seen. Other features. Most individuals have short stature and failure to thrive. Some individuals are slender and have a marfanoid habitus but no other features of Marfan syndrome. Course. Scoliosis is progressive and associated with loss of respiratory function in mid-later childhood, after which the course is often static.
Individuals may walk well into adulthood despite severe scoliosis and need for ventilatory support. In a few severe cases the disease may progress slowly through adolescence and adulthood, eventually leading to loss of ambulation.
Death often occurs as a result of respiratory infection in a setting of severe respiratory insufficiency.
Late onset of the disease is usually associated with better prognosis.Moderate form with hand involvement (<10%). The characteristic feature is distal weakness of the upper limbs with joint hyperlaxity. Distal lower limbs are relatively normal. Scoliosis and respiratory involvement are mild or absent. Antenatal form with arthrogryposis multiplex congenita (AMC) (<10%). The characteristic feature is generalized joint contractures at birth as a result of poor fetal movement. Associated distinctive features are dolicocephaly, prominent nasal root, oblique palpebral fissues, high-arched palate, low-set ears, short neck, and clinodactyly. Ophthalmoplegic form (<10%) usually presents in the neonatal period or early infancy with marked generalized hypotonia and weakness. Failure to thrive and pronounced weakness of the axial and proximal muscles are common. External ophthalmoplegia predominantly affects upward and lateral gaze. Ligaments are universally lax. Respiratory function is moderately impaired but nocturnal hypoventilation is usually not a finding [Jungbluth et al 2000, Jungbluth et al 2005].

Genotype-Phenotype CorrelationsSEPN1. Individuals with SEPN1 mutations have classic MmD. May develop early and severe scoliosis resulting in respiratory insufficiency requiring respiratory assistance [Ferreiro et al 2002b]. RYR1. The disease is usually milder than that caused by mutations in SEPN1. The forms of MmD associated with RYR1 mutations include the moderate form with hand involvement [Ferreiro et al 2002a] and the ophthalmoplegic form [Monnier et al 2003, Jungbluth et al 2005].

Differential DiagnosisAll forms of congenital myopathy have a number of common clinical features: generalized proximal weakness, hypotonia, hyporeflexia, poor muscle bulk, and features secondary to myopathy (e.g., elongated facies, high arched palate, pectus carinatum, scoliosis, foot deformities). Presence of severe rapidly progressive scoliosis favors a diagnosis of classic multiminicore disease (MmD); however, marked clinical overlap exists among MmD and congenital myopathies as well as other neuromuscular disorders including congenital muscular dystrophy. Therefore, the diagnosis of MmD rests on the presence of typical structural changes on muscle biopsy. Minicore lesions can coexist with central cores, rods or centrally located nuclei, and variable fibrosis. The differential diagnosis in those cases can include central core disease, nemaline myopathy, centronuclear myopathy, or one of the muscular dystrophies. Of these conditions, central core disease is most difficult to differentiate because minicores may be the predominant histopathologic finding in central core disease. In this situation, presence of pronounced hip girdle weakness, only mild facial involvement, lack of significant respiratory impairment, and myalgias or muscle cramps may support a diagnosis of central core disease. Central cores in central core disease have sharply defined boundaries, involve exclusively type I fibers, and extend throughout the entire fiber length, often centrally. However, it is important to remember that the differentiation between minicores and central cores is not always straightforward, and a continuum of histopathologic changes may be present in individuals.Dominant mutations in ACTA1 have been described in individuals with congenital myopathy with atypical cores (not typical of central cores or multiple minicores) and those with coexisting cores and nemaline rods [Jungbluth et al 2001, Kaindl et al 2004]. Nemaline bodies with cores have been described in a family with recessive CFL2 mutation [Agrawal et al 2007]. Similarly, a locus on chromosome 15q21-q23 has been linked to a dominantly inherited nemaline myopathy with core-like lesions [Gommans et al 2003].Secondary MmD. Multiple minicore lesions can also be secondary to other conditions including SCAD (short-chain acyl-COA dehydrogenase) deficiency, multiple pterygium syndrome with hypertrophic cardiomyopathy, other cardiomyopathies, hypohidrotic ectodermal dysplasia, Marfan syndrome, anesthetic reaction, and neurogenic conditions including denervation. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).MmD, classic form MmD, moderate form, with hand involvement MmD, antenatal form, with arthrogryposis multiplex congenita MmD, ophthalmoplegic form

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with multiminicore disease (MmD), the following evaluations are recommended:Comprehensive respiratory evaluation including assessment of breathing rate, signs of respiratory distress, ability to maintain oxygen saturations, pulmonary function studies, and sleep studies to rule out nocturnal hypoxia Assessment of feeding abilities including suck, swallow, gastroesophageal reflux, and maintenance of airway while feeding; evaluation of growth parameters to identify failure to thrive and determine need for interventions including gavage feeds and gastrostomy tube insertion Spinal x-rays to evaluate for presence of scoliosis; physical examination for joint contractures Cardiac evaluation for cardiomyopathy/cardiac involvement secondary to respiratory complications Physical and occupational therapy evaluation to develop interventions based on the distribution and extent of weakness Speech evaluation, especially if dysarthria or hypernasal speech is present Orthodontic evaluation for palatal anomalies Medical genetics consultationTreatment of ManifestationsTreatment is aimed at prevention of disease manifestations, early diagnosis by regular screening, and aggressive management of complications that may develop. Effective treatment requires a multidisciplinary approach that can improve both quality of life and survival for the affected individual.Ongoing careful assessment of the potential need for part-time or permanent respiratory support is absolutely critical, as affected individuals may rapidly enter respiratory crisis or may unknowingly suffer from potentially fatal nocturnal hypoventilation. Feeding support with tube/gavage feeds is needed if oral intake is poor. Failure to thrive may need to be overcome with high-caloric density formulas/feeds. Gastroesophageal reflux (if present) is treated in the usual manner.Physical and occupational therapy may help to improve/maintain gross motor and fine motor functions.Speech therapy should be provided for individuals with dysarthria/hypernasal speech.Prevention of Secondary ComplicationsAnnual influenza and other respiratory infection-related immunizations are advised.Aggressive treatment of lower respiratory infections is critical.SurveillanceMonitoring for potential complications that can influence the prognosis of MmD includes the following:Frequent and regular monitoring of the spine particularly during childhood and adolescence when scoliosis can rapidly progress during the adolescent growth spurt Careful monitoring of respiratory function from an early stage because of the risk for insidious nocturnal hypoxia and sudden respiratory failure. Monitoring of respiratory function should include the following: Close attention to nocturnal hypoventilation symptoms including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performanceLung function tests (FEV1 and FVC)Sleep studiesAssessment of the need for intermittent or permanent ventilation. Nocturnal ventilation, when indicated, may significantly improve the prognosis. Assessment of cardiac status because of the risk of cardiac impairment secondary to respiratory involvement Growth should be assessed regularly.Regular neuromuscular evaluation to assess disease progress is indicated.Agents/Circumstances to AvoidRisk for malignant hyperthermia. Depolarizing muscle relaxants (e.g., succinylcholine) and inhalational agents (e.g., halothane, isoflurane, desflurane) can cause malignant hyperthermia and therefore need to be avoided during surgical procedures/childbirth, as RYR1 mutations are associated with both malignant hyperthermia susceptibility and MmD. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management In women with MmD, there is risk for malignant hyperthermia during delivery if inhalational anesthetic agents are used. A woman who has a fetus affected by MmD may develop polyhydramnios during pregnancy and may report a history of poor fetal movements. Abnormal presentation of an affected fetus may complicate delivery. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Multiminicore Disease: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDRYR119q13​.2Ryanodine receptor 1RYR1 homepage - Leiden Muscular Dystrophy pagesRYR1SEPN11p36​.11Selenoprotein NSEPN1 homepage - Leiden Muscular Dystrophy pagesSEPN1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Multiminicore Disease (View All in OMIM) View in own window 117000CENTRAL CORE DISEASE OF MUSCLE 180901RYANODINE RECEPTOR 1; RYR1 255320MINICORE MYOPATHY WITH EXTERNAL OPHTHALMOPLEGIA 602771RIGID SPINE MUSCULAR DYSTROPHY 1; RSMD1 606210SELENOPROTEIN N, 1; SEPN1 607552MINICORE MYOPATHY, ANTENATAL ONSET, WITH ARTHROGRYPOSISSEPN1 Normal allelic variants. SEPN1 has 13 exons spanning 18.5 kb. The transcription product is 4.5 kb and the open reading frame has 1770 nucleotides. The functional transcript has one in-frame TGA codon in exon 10, which is read as selenocysteine because of the presence of a selenocysteine insertion sequence (SECIS) element in the 3' UTR region. Known non-pathogenic polymorphisms are included in Table 2 (pdf). Pathologic allelic variants. The pathologic mutations in SEPN1 associated with MmD are summarized in Table 3 (pdf) [Ferreiro et al 2002a, Ferreiro et al 2002b, Tajsharghi et al 2005, Zorzato et al 2007]. Up to two thirds of mutations cause premature termination of translation; the remaining mutations are missense changes. Mutations appear to be distributed throughout the gene. Normal gene product. The gene encodes a 590-amino acid protein called selenoprotein N. The function of selenoprotein N is not known, but it is found in virtually all tissues examined by western blot. The protein is expressed in very low levels and most studies require overexpression. An enzymatic function has been hypothesized for selenoprotein N based on protein structure and analogies with other selenoproteins with known function. Most of the selenoproteins identified to date are catalysts either in redox processes or in thyroid hormone processing. Selenoprotein N has an EF hand Ca²⁺ binding motif similar to that found in proteins like calmodulin, suggesting that Ca²⁺ may play a role in Ca homeostasis and/or in modulation of selenoprotein N function.Abnormal gene product. The abnormal gene product either is a truncated protein or may contain a missense amino acid substitution. The functional significance of these abnormal products is unknown. SEPN1 mRNAs associated with frameshift or nonsense mutations may be resistant to nonsense-mediated decay [Okamoto et al 2006]. RYR1 Normal allelic variants. RYR1 has 106 exons encompassing a total of 160 kb. Pathologic allelic variants. More than 25 missense dominant mutations in RYR1 have been associated with malignant hyperthermia susceptibility and/or central core disease [Galli et al 2002]. Mutations in RYR1 associated with MmD described to date have been homozygous (see Table 4 [pdf]) [Ferreiro et al 2002a, Jungbluth et al 2002, Jungbluth et al 2005, Zhou et al 2007, Zorzato et al 2007].Zhou et al [2006] found that RYR1 undergoes polymorphic, tissue-specific, and developmentally regulated allele silencing, and this unveils recessive mutations in individuals with core myopathies.Normal gene product. RYR1 encodes ryanodine receptor 1, the calcium release channel of skeletal muscle sarcoplasmic reticulum. Ryanodine receptor 1 is one of the largest known proteins, with 5038 amino acids. The functional channel is composed of four identical subunits of 565 kd each and has been shown to interact with a number of regulatory proteins. The first 4000 amino acids comprise the hydrophilic cytoplasmic domain that bridges the gap between the transverse tubules and sarcoplasmic reticulum; the last 1000 amino acids form the hydrophobic membrane-spanning plate containing the pore [Tilgen et al 2001]. Abnormal gene product. Most RYR1 mutations associated with malignant hyperthermia (MH) and central core disease (CCD) affect calcium homeostasis by either making the calcium channels hypersensitive to activation (associated with MH) or decreasing the amount of calcium released after activation (CCD phenotype) [Dulhunty et al 2006]. Studies on RYR1 mutations associated with MmD phenotype have shown variable dysregulation of calcium homeostasis. While the p.Pro3527Ser mutation caused decreased calcium release after stimulation, there was no reduction in the case of the p.Ser71Tyr mutation, and increased calcium release was noted with the p.Asn2283His mutation. One hypothesis is that these mutations cause instability of the ryanodine receptor macromolecular complex leading to altered binding of regulatory proteins. In contrast, the mutations p.Arg109Trp, p.Met485Val, and the 14646+2.99 kb intronic splicing variant are associated with very low endogenous ryanodine receptor protein levels [Ducreux et al 2006, Zorzato et al 2007].